The present invention relates to a device for iontophoretic delivery of active ingredients to a patient. The invention also relates to a method for iontophoretic delivery of active ingredients to a patient, and to a method for reducing the possibility of skin trauma caused by iontophoretic delivery of active ingredients to a patient.
Iontophoretic drug delivery is based on the principle that charged molecules will migrate in an electric field toward the electrode of opposite charge. In practice, the process of iontophoretic drug delivery is performed by putting a solution of the drug, often contained in a piece of filter paper or in a gel or in some other device to contain the solution, onto intact skin. The solution is then covered by an electrode. A second electrode is placed elsewhere on the skin, and a direct current source is connected between the two electrodes in such a way that the electrode in contact with the drug solution assumes the same charge as the ionized drug. Under the influence of the electric field present, drug molecules migrate through the skin. A current flows between the electrodes, part of which is carried by the drug.
Although the process of iontophoretic drug delivery may be accomplished using very simple electrodes, certain advantages accrue through the use of more sophisticated electrode configurations. For example, one side effect of the iontophoretic process is the possible formation of vesicles and bullae on the skin beneath the electrodes, as described by W. B. Shelley et al. in J. Invest. Dermatol., 11, pg. 275 (1948). Minimization of this type of skin trauma has been the subject of several recent patents. Jacobsen et al. in U.S. Pat. No. 4,416,274 describe a segmented electrode which is designed to ensure uniform current flow, thereby minimizing skin trauma arising from high localized currents.
In another series of patents, U.S. Pat. Nos. 4,166,457, 4,250,878, and 4,477,971, Jacobsen et al. describe electrodes to which a solution of a drug may be added just prior to the application of the iontophoretic treatment to the patient. The salient feature of these electrodes is that they have an empty chamber closed on the side which is to be attached to the skin by a microporous membrane, which allows the iontophoretic passage of ions but inhibits fluid flow under modest pressure differentials. These electrode designs contain self-sealing devices which allow addition of the drug solution, similar in function to the rubber septa commonly used in medical practice in the manipulation of parenteral solutions. These electrodes employ clothing snaps to provide electrical contact with the external circuit, also a common practice with the use of electrocardiographs and other medical devices which require electrical contact with the skin. One important factor in the use of these electrodes is to ensure that gas bubbles (either from gas originally present in the electrode or from that which is formed by the electrode reaction) do not interfere with the electrical contact between the drug solution and the clothing snap.
Addition of the drug solution to the electrode at the time of application of iontophoretic treatment to the patient provides several advantages. One electrode may be used for delivery of several different drugs. Further, since many of the drugs for which iontophoretic delivery is practical are available in parenteral form, the parenteral form of the drug can often be used without modification.
None of these recent patents concerning the design and construction of iontophoretic electrodes identify or address the problem of pH control in the electrodes. Protons are produced at the anode and hydroxide ions are produced at the cathode by water electrolysis under the usual conditions employed in iontophoretic drug delivery. The ion produced in the drug solution has the same charge as the drug, and if the ion is allowed to accumulate in the solution it will begin to compete with the drug as the treatment proceeds. Another factor which also appears to be pH related is the maximum current density which may be passed through the skin. The maximum current is the maximum current density times the electrode area employed. The penalties for exceeding the maximum permissible current density are pain and burns. Molitor and Fernandez, Am. J. Med. Sci., 198, pg. 778 (1939) reported that the maximum permissible current density is not independent of electrode area. We observe similar behavior. The data from Molitor and Fernandez, on the maximum current which can be applied from an effectively unbuffered but relatively constant pH electrode to the skin for fifteen minutes without causing pain, as a function of area, are shown in FIG. 1. The points are taken from the aforementioned reference. The line of FIG. 1 was derived from a model which says that the pain is derived from the buildup of a substance in the skin, the generation of which is proportional to current and the dissipation of which is proportional to the concentration. The derivation of the equation of the line, fit to the endpoints of the data, is given below. The fit of the data appears to support this hypothesis. ##EQU1##
Using the endpoints of the Molitor et al. data (A=25, Q=10 and A=500, Q=26.5) yields a value for L of 29.0 and for M of 47.55. Thus i=29.0A/47.55+A. A comparison of the Molitor et al. experimental values and those calculated from the above equation appear below and are plotted in FIG. 1 as noted above.
______________________________________ Area cm.sup.2 Experimental (m Amps) Calculated ______________________________________ 25 10.0 (10.0) 50 14.0 14.9 75 17.0 17.8 100 19.0 19.6 125 20.5 21.0 150 21.5 22.0 175 22.5 22.8 200 23.0 23.4 225 23.8 23.9 250 24.2 24.4 275 24.7 24.7 300 25.2 25.0 400 26.3 25.9 500 26.5 (26.5) ______________________________________
Time is also a factor affecting the maximum permissible current density. In Table I below is presented the maximum time for an iontophoretic experiment as determined by a drop in skin resistance under a weakly buffered electrode as a function of current density. A significant drop in skin resistance is indicative of skin trauma. Also presented is the total charge passed, which is related to the product of the current and the time.
TABLE I ______________________________________ Maximum Time for Iontophoresis as a Function of Current Current Time Charge ______________________________________ 5.0 mA 36 min 10.8 coulombs 2.0 mA 72 min 8.6 coulombs 1.5 mA 110 min 9.9 coulombs ______________________________________
At a given current an experiment could only be run for the specified length of time. The time increased with decreasing current in such a way that the product of the two, the total charge, remained relatively constant. Molitor (Merck Report, Jan. 22, 1943) hypothesizes that the factor which limits the current density is the buildup of protons or hydroxyl ions in the subcutaneous tissue as evidenced by a change in pH. Molitor and Fernandez had shown that a change in subcutaneous pH of 1.5 pH units can occur after fifteen minutes of iontophoresis.
This hypothesis is consistent with the data in Table I as well, if one assumes that the reason why the subcutaneous pH beneath an anode drops more or less linearly for fifteen minutes is not that steady state between proton generation and dissipation is reached this slowly, but rather that increase in proton concentration in the subcutaneous tissue is due to increasing proton transport from the donor solution as the buffer capacity of the donor solution is strained by the continuous production of protons at the anode. For example, the data in Table I were generated using physiological saline buffered with 0.01M phosphate. By using 0.5M phosphate as the electrolyte at both electrodes, operation at 2 mA for at least two hours was possible without experiencing a drop in skin resistance. It appears, therefore, that pH control, in addition to being a major factor in optimizing current efficiency, is also a major factor in enabling the use of high current densities and/or long iontophoretic durations without discomfort or skin trauma.
Accordingly, there is a continuing need for an efficient and safe iontophoretic drug delivery device that inhibits the current carrying capacity of ions that compete with the active ingredient.